The diagnostic imaging based on the Nuclear Magnetic Resonance principles, which includes the Magnetic Resonance Imaging (MRI) and the Magnetic Resonance Spectroscopy Imaging (MRSI), herein after collectively indicated as MRI, is a well established imaging method which represents a powerful tool for everyday clinical investigations.
The large majority of MRI procedures deals with the very intense water signal, the concentration of which in the human body is about 55.6 M. In most cases, 1H-MR images of the examined organ or body tissue correspond to a topological representations of differences in water density and/or relaxation rates of water protons into the region of clinical interest.
The contrast in these images can be augmented by the use of specific substances, known as contrast agents for MRI, modifying the relaxation times, T1 and T2, of water protons.
Because of their ability to affect relaxation times, many paramagnetic substances have potential as contrast agents. In practice, however, only metal complexes or cluster complexes that are paramagnetic as a result of containing one or more unpaired electrons are used as MRI paramagnetic contrast agents.
The most important class of contrast agents for MRI is represented by paramagnetic chelates, especially those containing one of the following paramagnetic ions: Gd(III), Mn(II), Fe(III) and Cr(III).
Their effect on the relaxation rate of water protons is usually assessed through the determination of their relaxivity (r1), i.e. the relaxation enhancement of water protons promoted by the paramagnetic complex at 1 mM concentration, measured at a given observation frequency (often 20 MHz) and temperature (usually 39° C.).
The relaxivity r1 of a given paramagnetic complex may be considered as the sum of different contributions reflecting the different interaction modalities between water protons and the paramagnetic center.
The most important of these contributions, r1is, directly depends on the ratio between the concentration of water bound to the given paramagnetic chelate complex and the total concentration of water, and inversely depends on the sum of the relaxation time T1M and the residence time τM of the protons of the water molecule(s) coordinated to the paramagnetic chelate complex, according to the following equation:
      r    1    is    =                              [                                    H              2                        ⁢            O                    ]                bound                              [                                    H              2                        ⁢            O                    ]                total              ⁢                  ⁢          1                        T                      1            ⁢            M                          +                  τ          M                    
In this formula [H2O]bound corresponds to the concentration of the given paramagnetic complex times the number (q) of water molecules directly coordinated to the metal centre. Since in most cases q=1 and [H2O]total=55.6 M, for 1 mM concentration of the paramagnetic chelate, the ratio [H2O]bound/[H2O]total is a fixed value (1.8·10−5). This means that, in the case of MR images of the water signal, this ratio cannot be increased to a greater extent.
Most paramagnetic metal complexes have been developed for MRI methods based on the resonance of 1H water protons: examples of said complexes and their use in conventional 1H water protons magnetic resonance imaging methods are reported, inter alia, in WO 00/38738, U.S. Pat. No. 5,977,353, FR 2725449, FR 2802928 and in J. Alloys and Compounds, 249(1997) 185-190.
A relatively small portion of MRI clinical applications deals with imaging of resonances of 1H protons other than the 1H water protons.
In such cases, attention has been focused on species present in relatively large amount like the fatty constituents present in many tissues (E. L. Thomas and J. D Bell in “Methods in Biomedical Magnetic Resonance Imaging and Spectroscopy”, Wiley; 2000. Vol. 2, p 837-845 and references therein), or in the use of sophisticated and dedicated techniques and equipments (EP-A-370333 for the in vivo lactate visualization).
Also the acquisition of MR images of nuclei different from protons is rather uncommon in biological systems. First of all, it is not easy to find in such systems magnetically active nuclei, i.e. nuclei with nuclear spin ≠0, naturally present at sufficiently high concentration or whose enrichment in the isotope of interest is practically feasible.
Secondly, and mainly, the relaxation times of these magnetically active nuclei other than 1H often exceeds one second, making very time consuming the accumulation of the number of transients to yield a sufficient signal to noise ratio (SNR) for obtaining a good image.
In general, in fact, the generation of a good substrate imaging in a reasonable time requires dealing with signal characterized by short T1, in order to accumulate a high number of transients enhancing thereby the signal to noise ratio.
Nonetheless, the possibility of recording images of nuclei different from water protons appears highly attractive because the absence of signal from background is certainly very useful for improving the diagnostic content of the resulting MR image.
Moreover, there are a number of endogenous substances whose imaging would be extremely interesting and useful from the clinical point of view. A non-limiting list of such substances includes metabolites and substrates like lactate, citrate, carbonate, phosphate, pyruvate, natural amino-acids, oxalate, tartrate, succinate, choline, creatine, acetate, malonate. These molecules are involved in several human metabolic processes and changes in their normal production, as well as in their biodistribution, may be generally related to pathologic conditions.
Lactate, for example, is an endogenous metabolite of particular diagnostic relevance. It is an end product of the anaerobic glycolysis and, therefore, an increase of its concentration in tissues may be a clear indication of hypoxia, as it is found in some solid tumors. High levels of lactate are further present in conditions of reduced blood flow occurring in cerebral strokes or coronary infarcts or in presence of metabolic disorders or type I diabetes.
Another important metabolite, whose in vivo mapping would be very useful, is citrate. Its concentration in the case of prostatic tumor differs significantly between benign prostatic hyperplasia (BPH, high concentration) and malignant prostatic carcinoma (low concentration).
Hence, there remains a need for a Magnetic Resonance Imaging method which would allow the imaging of molecules different from water in a time suitable for a conventional medical practice and by conventional mode of operation.